Therapeutic compounds

ABSTRACT

Compounds comprising 
                         
or a pharmaceutically acceptable salt or a prodrug thereof, are disclosed, wherein J, B, Y, and A are as described.
 
     Methods, compositions, and medicaments related thereto are also disclosed.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/051,753, filed May 9, 2008, the disclosure of which is herebyincorporated in its entirety herein by reference.

DESCRIPTION OF RELATED ART

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandin EP₂ selective agonists are believed to have severalmedical uses. For example, U.S. Pat. No. 6,437,146 teaches the use ofprostaglandin EP₂ selective agonists “for treating or preventinginflammation and pain in joint and muscle (e.g., rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenilearthritis, etc.), inflammatory skin condition (e.g., sunburn, burns,eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Chrohn's disease, atrophicgastritis, gastritis varialoforme, ulcerative colitis, coeliac disease,regional ileitis, irritable bowel syndrome, etc.), gingivitis,inflammation, pain and tumescence after operation or injury, pyrexia,pain and other conditions associated with inflammation, allergicdisease, systemic lupus crythematosus, scleroderma, polymyositis,tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren'ssyndrome, Behcet disease, thyroiditis, type I diabetes, diabeticcomplication (diabetic microangiopathy, diabetic retinopathy, diabeticneohropathy, etc.), nephrotic syndrome, aplastic anemia, myastheniagravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,sarcoidosis, Hodgkin's disease, Alzheimers disease, kidney dysfunction(nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis,cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatorybowel disease, etc.) shock, bone disease characterized by abnormal bonemetabolism such as osteoporosis (especially, postmenopausalosteoporosis), hypercalcemia, hyperparathyroidism, Paget's bonediseases, osteolysis, hypercalcemia of malignancy with or without bonemetastases, rheumatoid arthritis, periodonritis, osteoarthritis,ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis(especially, urolithiasis), solid carcinoma, mesangial proliferativeglomerulonephritis, edema (e.g. cardiac edema, cerebral edema, etc.),hypertension such as malignant hypertension or the like, premenstrualtension, urinary calculus, oliguria such as the one caused by acute orchronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

SUMMARY OF THE INVENTION

Disclosed herein are compounds useful in treating glaucoma, inflammatorybowel disease, the stimulation of hair growth, and the stimulation ofthe conversion of vellus hair to terminal hair. The compounds themselvesare disclosed below.

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   J is C═O, CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN; and-   B is substituted aryl or heteroaryl    with the proviso that the compound is not

In another embodiment, the compound is not

Also disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   J is C═O, CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN; and-   B is C₁₋₁₀ oxoalkyl substituted aryl or heteroaryl.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be a moiety where S replaces one or two carbon atoms such as one ofthe following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way,

in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar, e.g.—CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—, —(CH₂)₂—Ar—(CH₂)₂—,and the like; in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂moieties; and Ar, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,—O—CH₂—Ar—(CH₂)₂, and the like; or in another embodiment A comprises: S;0, 1, 2, or 3 CH₂ moieties; and Ar, e.g., —S—Ar—, Ar—CH₂—S—,—S—Ar—(CH₂)₂—, —S—CH₂—Ar—, —S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.”

Thus, the substituent may be hydrocarbyl having up to 4 carbon atoms,including alkyl up to C₄, alkenyl, alkynyl, and the like;

-   hydrocarbyloxy up to C₃;-   organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and salts    thereof;-   CF₃;-   halo, such as F, Cl, or Br;-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents such as CN, NO₂, and the like;-   and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is 1, 2, or 3, and wherein one CH₂may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar isattached at the 1 and 3 positions, otherwise known as m-interphenylene,such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂—O—(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH2)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below, andpharmaceutically acceptable salts thereof, and prodrugs thereof, arecontemplated as individual embodiments. In other words, each structurerepresents a different embodiment.

J is C═O, CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN. Thus, eachstructure depicted below represents a compound embodiment which isindividually contemplated. Pharmaceutically acceptable salts andprodrugs of compounds according to the structures below are alsocontemplated.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt.

Thus, while not intending to limit the scope of the invention in anyway, a substituent may be:

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, alkenyl, alkynyl, and the like, including linear,    branched or cyclic hydrocarbyl, and combinations thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 19 carbon atoms;-   other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the    like; thioether substituents including S-hydrocarbyl and other    thioether substituents;-   hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,    etc, up to 19 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 19    carbon atoms;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like fluorocarbyl,    such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl. For this type ofpolycyclic ring system, an aromatic or heteroaromatic ring, not anon-aromatic ring, must be attached to the remainder of the molecule. Inother words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring.

In one embodiment, B is substituted aryl or heteroaryl.

In another embodiment B is substituted phenyl.

In another embodiment B has no halogen atoms.

In another embodiment B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxybutyl)phenyl.

In another embodiment B is 4-(1-hydroxyheptyl)phenyl.

In another embodiment B is 4-(1-hydroxyhexyl)phenyl.

In another embodiment B is 4-(1-hydroxypentyl)phenyl.

In another embodiment B is 4-(1-hydroxypropyl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

In another embodiment B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

In another embodiment B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-tert-butylphenyl.

In another embodiment B is 4-hexylphenyl.

In another embodiment B is 4-(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxycyclobutyl)phenyl.

In another embodiment B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

In another embodiment B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

In another embodiment B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

In another embodiment B is 4-(cyclohexylmethyl)phenyl.

In another embodiment B is 4-(hydroxy(phenyl)methyl)phenyl.

Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

-   Alkyl is hydrocarbyl having no double or triple bonds including:-   linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl,    n-hexyl, and the like;-   branched alkyl such as isopropyl, branched butyl isomers (i.e.    sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e.    isopentyl, etc), branched hexyl isomers, and higher branched alkyl    fragments;-   cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.; and-   alkyl fragments consisting of both cyclic and noncyclic components,    whether linear or branched, which may be attached to the remainder    of the molecule at any available position including terminal,    internal, or ring carbon atoms.-   Alkenyl is hydrocarbyl having one or more double bonds including    linear alkenyl, branched alkenyl, cyclic alkenyl, and combinations    thereof in analogy to alkyl.-   Alkynyl is hydrocarbyl having one or more triple bonds including    linear alkynyl, branched alkynyl, cyclic alkynyl and combinations    thereof in analogy to alkyl.-   Aryl is an unsubstituted or substituted aromatic ring or ring system    such as phenyl, naphthyl, biphenyl, and the like. Aryl may or may    not be hydrocarbyl, depending upon whether it has substituents with    heteroatoms.-   Arylalkyl is alkyl which is substituted with aryl. In other words    alkyl connects aryl to the remaining part of the molecule. Examples    are —CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may    not be hydrocarbyl, depending upon whether it has substituents with    heteroatoms.    Unconjugated dienes or polyenes have one or more double bonds which    are not conjugated. They may be linear, branched, or cyclic, or a    combination thereof. Combinations of the above are also possible.

Oxoalkyl is alkyl wherein one carbon atom is C═O. C₁₋₁₀ oxoalkyl isoxoalkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Theoxyalkyl moiety may also form a ring with the aryl or heteroaryl group.Thus, for example, B may be substituted or unsubstituted tetralonyl,indanonyl, or the like.

In another embodiment B is C₁₋₁₀ oxoalkyl substituted phenyl.

Thus, each of the structures below is contemplated. These structures, orpharmaceutically acceptable salts thereof, or prodrugs thereof,individually represent a compound which is an embodiment contemplatedherein. In other words, each structure represents a differentembodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

Hypothetical examples of useful compounds are shown below.

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   J is C═O, CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN; and-   B is C₁₋₁₀ oxoalkyl substituted aryl or heteroaryl.

Compound Example 2

The compound according to example 1 wherein B is substituted phenyl.

Compound Example 3

The compound according to example 1 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 4

The compound according to compound example 3 wherein R is alkyl.

Compound Example 5

The compound according to compound example 3 wherein R is arylalkyl.

Compound Example 6

The compound according to compound example any one of compound examples1 to 5 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 7

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein Y is an organic acid functional group, or an amide or ester    thereof comprising up to 14 carbon atoms; Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O;-   J is C═O, CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN; and-   B is substituted aryl or heteroaryl with the proviso that the    compound is not

wherein Y¹ is CO₂H or an amide or a carboxylic acid.

Compound Example 8

The compound according to any one of compound examples 1 to 7 wherein Ais (3-methylphenoxy)methyl.

Compound Example 9

The compound according to any one of compound examples 1 to 7 wherein Ais (4-but-2-ynyloxy)methyl.

Compound Example 10

The compound according to any one of compound examples 1 to 7 wherein Ais 2-(2-ethylthio)thiazol-4-yl.

Compound Example 11

The compound according to any one of compound examples 1 to 7 wherein Ais 2-(3-propyl)thiazol-5-yl.

Compound Example 12

The compound according to any one of compound examples 1 to 7 wherein Ais 3-methoxymethyl)phenyl.

Compound Example 13

The compound according to any one of compound examples 1 to 7 wherein Ais 3-(3-propylphenyl.

Compound Example 14

The compound according to any one of compound examples 1 to 7 wherein Ais 3-methylphenethyl.

Compound Example 15

The compound according to any one of compound examples 1 to 7 wherein Ais 4-(2-ethyl)phenyl.

Compound Example 16

The compound according to any one of compound examples 1 to 7 wherein Ais 4-phenethyl.

Compound Example 17

The compound according to any one of compound examples 1 to 7 wherein Ais 4-methoxybutyl.

Compound Example 18

The compound according to any one of compound examples 1 to 7 wherein Ais 5-(methoxymethyl)furan-2-yl.

Compound Example 19

The compound according to any one of compound examples 1 to 7 wherein Ais 5-(methoxymethyl)thiophen-2-yl.

Compound Example 20

The compound according to any one of compound examples 1 to 7 wherein Ais 5-(3-propyl)furan-2-yl.

Compound Example 21

The compound according to any one of compound examples 1 to 7 wherein Ais 5-(3-propyl)thiophen-2-yl.

Compound Example 22

The compound according to any one of compound examples 1 to 7 wherein Ais 6-hexyl.

Compound Example 23

The compound according to any one of compound examples 1 to 7 wherein Ais (Z)-6-hex-4-enyl.

Compound Example 24

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)thiophen-2-yl.

Compound Example 25

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)thiophen-3-yl.

Compound Example 26

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)furan-2-yl.

Compound Example 27

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)furan-3-yl.

Compound Example 28

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)pyridin-2-yl.

Compound Example 29

The compound according to any one of compound examples 7 to 23 wherein Bis 3-(1-hydroxyhexyl)pyridin-3-yl.

The following are hypothetical examples of compositions, kits, methods,uses, and medicaments employing the hypothetical compound examples.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 29, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 29 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Use of a compound according to any one of compound examples 1 to 29 inthe manufacture of a medicament for the treatment of baldness in amammal.

A medicament comprising a compound according to any one of compoundexamples 1 to 29, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 29 to a mammal for the treatment of glaucoma orocular hypertension.

A method comprising administering a compound according to any one ofcompound examples 1 to 29 to a mammal for the treatment of baldness.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 29, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 29, a container, and instructions foradministration of said composition to a mammal for the treatment ofbaldness.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

Applications for Stimulating Hair Growth

In one embodiment, the compounds disclosed herein can be useful in thetreatment of baldness and/or hair loss. Alopecia (baldness) is adeficiency of either normal or abnormal hair, and is primarily acosmetic problem in humans. It is a deficiency of terminal hair, thebroad diameter, colored hair that is readily seen. However, in the socalled bald person, although there is a noticeable absence of terminalhair, the skin does contain vellus hair, which is a fine colorless hairwhich may require microscopic examination to determine its presence.This vellus hair is a precursor to terminal hair.

The compounds described herein can be used to stimulate, such as theconversion of vellus hair to growth as terminal hair, as well asincreasing the rate of growth of terminal hair. The utility of thecompounds described herein for the simulation of hair growth wasdiscovered as follows.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice, it wasdiscovered that a patient who had been treated with bimatoprost, aprostaglandin analogue, developed lashed that were longer, thicker, andfuller in the treated eye than in the non-treated eye. On examination,the difference was found to be very striking. The lashes were longer andhad a fuller, denser appearance in the treated eye. The lash appearanceon the lids of the treated eyes would have appeared quite attractive ifit represented a bilateral phenomenon. As a result of its asymmetricnature, the long lashes on one side could be construed as disturbingfrom a cosmetic standpoint. A systemic examination was preformed as aresult of the asymmetric phenomenon. It soon became apparent that thisaltered appearance was not an isolated finding. Comparison of the lidsof patients who were taking bimatoprost in only one eye revealed subtlechanges in the lashed and adjacent hairs of the bimatoprost-treated sidein several patients. Definite differences could be identified to varyingdegrees in the lashes and adjacent hairs of all patients who were takingthe drug on a unilateral basis for longer than 6 months.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of glaucoma follow-up examination,attention is generally immediately focused on the eye itself. As aresult of the high power magnification needed only one eye is seen at atime and the eye is seen at a high enough power that the lashes are notin focus. At these higher powers, any lash asymmetry between the twoeyes is not likely to be noticed except by careful systematic comparisonof the lashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treatment area following administration of theprostaglandin analogue were multiple. They included increased length oflashed, increased number of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased auxiliary lash-like terminal hairs at the medial and lateralcanthal area, increased pigmentation of the lashes, increased numbers,increased length, as well as increased luster, and thickness of finehair on the skin of the adjacent lid, and finally, increasedperpendicular angulation of lashes and lash-like terminal hairs. Theconclusion that hair growth is stimulated by prostaglandin analoguessuch as bimatoprost is thus supported not by evidence of a difference ina single parameter, but is based on multiple parameters of hairappearance in treated versus control areas in many subjects.

The compounds described herein are prostaglandin analogues and thereforehave similar activities as bimatoprost, contain structural similarities,and therefore are expected to stimulate hair growth and stimulation ofthe conversion of vellus hair to terminal hair. In one embodiment, thecompounds described herein and their prodrugs can be used for thestimulation of hair growth. As used herein, hair growth includes hairassociated with the scalp, eyebrows, eyelids, beard, and other areas ofthe skin of animals.

In one embodiment, the compound is mixed with a dermatologicallycompatible vehicle or carrier. The vehicle, which may be employed forpreparing compositions as described herein, may comprise, for example,aqueous solutions such as e.g., physiological salines, oil solutions, orointments. The vehicle furthermore may contain dermatologicallycompatible preservatives such as e.g., benzalkonium chloride,surfactants like e.g., polysorbate 80, liposomes or polymers, forexample, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone andhyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated fortopical treatment for the stimulation of hair growth which comprises aneffective hair growth simulating amount of one or more compounds asdefined above and a dermatologically compatible carrier. Effectiveamounts of the active compounds may be determined by one of ordinaryskill in the art, but will vary depending on the compound employed,frequency of application and desired result. The compound will generallyrange from about 0.0000001 to about 50% by weight of the dermatologicalcomposition. Preferably, the compound will range from about 0.001 toabout 50% by weight of total dermatological composition, more preferablyfrom about 0.1 to about 30% by weight of the composition.

In one embodiment, the application of the present compounds forstimulation of hair growth finds applications in mammalian species,including both humans and animals. In humans, the compounds describedherein can be applied for example, to the scalp, face beard, head, pubicarea, upper lip, eyebrows, and eyelids. In animal raised for theirpelts, e.g., mink, the compounds described herein can be applied overthe entire surface of the body to improve the overall pelt forcommercial reasons. The process can also be used for cosmetic reasons inanimals, e.g., applied to the skin of dogs and cats having bald patchesdue to mange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated for the stimulation of hairgrowth include pharmaceutical compositions suited for topical and localaction. The term “topical” as employed herein relates to the use of acompound, as described herein, incorporated in a suitable pharmaceuticalcarrier, and applied at the site of thinning hair or baldness forexertion of local action. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds can be applied repeatedly for the sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, skin or scalp. The preferred dosageregimen will generally involve regular, such as daily, administrationfor a period of treatment of at least one month, more preferably atleast three months, and most preferably, at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments, or oils exhibitingphysologicla acceptable osmolarity by addition of pharmaceuticallyacceptable buffers and salts. such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid andthe like as additives. Furthermore, particularly aqueous solutions maycontain viscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matricies may also be employed as well assoluble and insoluble ocular inserts, for instance, based on substancesforming in situ gels. Depending on the actual formation and compound tobe used, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matricies for the slowrelease delivery may also be used. Typically, the dose to be applied onthe scalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The synthetic methods disclosed in U.S. patent application Ser. No.11/009,298, filed Dec. 10, 2004, and U.S. Provisional Patent ApplicationNo. 60/742,779, filed Dec. 6, 2005, both of which are expresslyincorporated by reference herein, may be readily adapted by one ofordinary skill in the art to obtain the compounds disclosed herein.

Compounds wherein J is CN compounds may be prepared by adapting theprocedure disclosed in U.S. Provisional Patent Application No.60/747,835, filed May 22, 2006.

Compounds wherein J is CHF may be prepared by adapting the proceduresdisclosed in U.S. patent application Ser. No. 11/009,298 and U.S.Provisional Patent Application No. 60/742,779.

Compounds wherein J is CHBr may be prepared by adapting the proceduresdisclosed in Tani, K. et. al. (ONO) Bioorganic and Medicinal Chemistry2002, 10, 1883.

Compounds wherein J is CCl₂ or CBr₂ may be prepared by adapting theprocedures disclosed in cite United States Provisional PatentApplication No. 60746275, filed on May 3, 2006, which is expresslyincorporated herein by reference.

Compounds wherein J is CF₂ be made from the corresponding compoundswhere J is C═O in a similar procedure to making compounds wherein J isCHF according to Lal et. al. J. Org. Chem. 1999, 64, 7048.

Synthetic Examples

-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid methyl ester (1). Compound 1 was synthesized as described in    U.S. Provisional Patent Application No. 60/742,779.-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-hexanoyl-phenyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid methyl ester (2). DDQ (13 mg, 0.056 mmol) was added to a    solution of 1 (23 mg, 0.052 mmol) in dichloromethane (1 mL)/H₂O (50    μL). After 6 h, more DDQ (16 mg) and dichloromethane (1 mL)/H₂O (50    μL) were added. The resulting mixture was allowed to stir overnight    and then 5 mL saturated NaHCO₃ solution was added. The mixture was    extracted with dichloromethane (3×30 mL) and the combined    dichloromethane solution was dried (Na₂SO₄), filtered and    evaporated. Purification of the residue by flash chromatography on    silica gel (20% ethyl acetate/hexanes) gave compound 2 (13 mg, 57%).-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-hexanoyl-phenyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid (3). The LiOH hydrolysis procedure described in U.S. patent    application Ser. No. 11/009,298.    Compound 4a and 4b.

Compound 4a. Triethylamine and ethyl chloroformate are addedsequentially to a solution of compound 3 in CH₂Cl₂ at room temperature.After 2.5 h, triethylamine and ethylene glycol are added. After stirringovernight at room temperature, the reaction mixture is partitionedbetween H₂O and CH₂Cl₂. The phases are separated and the aqueous phaseis extracted with CH₂Cl₂ (2×). The combined organic phase is washed with1 N HCl then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(10% CH₃OH/CH₂Cl₂) affords compound 4a.

Compound 4b. Triethylamine and ethyl chloroformate are addedsequentially to a solution of compound 3 in CH₂Cl₂ at room temperature.After 2.5 h, triethylamine and 4-(2-hydroxyethyl)-morphine are added.After stirring overnight at room temperature, the reaction mixture ispartitioned between H₂O and CH₂Cl₂. The phases are separated and theaqueous phase is extracted with CH₂Cl₂ (2×). The combined organic phaseis washed with 1 N HCl then dried (MgSO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (10% CH₃OH/CH₂Cl₂) affords compound 4b.

The following compounds can be useful according to the presentdescription.

In Vivo Examples

Compounds such as those described in the above are tested in vivo tomeasure its ability to reduce intraocular pressure. Compound 1 is testedin normotensive dogs. The intraocular pressure (IOP) decreases frombaseline. This compound is also tested in laser-induced hypertensivemonkeys, the IOP decreases from baseline.

Compound 2 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 3 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 4 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 5 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 6 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 7 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 8 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.” Unlessstereochemistry is explicitly depicted, a structure is intended toinclude every possible stereoisomer, both pure or in any possiblemixture. Unless stereochemistry is explicitly depicted, a structure isintended to include every possible stereoisomer, both pure or in anypossible mixture.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound which is a structure

or a pharmaceutically acceptable salt thereof; wherein Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; J is C═O,CHOH, CHF, CHCl, CHBr, CF₂, CCl₂, CBr₂, or CHCN; and B is C₁₋₁₀ oxoalkylsubstituted aryl or heteroaryl.
 2. The compound of claim 1 wherein A hasa structure selected from:


3. The compound of claim 2 wherein A is 5-(3-propyl)thiophen-2-yl. 4.The compound of claim 1 wherein A is 6-hexyl.
 5. The compound of claim 1wherein A is (Z)-6-hex-4-enyl.
 6. The compound of claim 1 wherein B is asubstituted phenyl.
 7. The compound of claim 1 which is a structure

or pharmaceutically acceptable salt thereof; wherein R is a hydrogen orC₁₋₁₀ hydrocarbyl.
 8. The compound of claim 1 which is a structure

or pharmaceutically acceptable salt thereof; wherein R is a hydrogen orC₁₋₁₀ hydrocarbyl.
 9. The compound according to claim 8 wherein R isalkyl.
 10. The compound according to claim 8 wherein R is arylalkyl. 11.The compound according to claim 1 which is a structure

or pharmaceutically acceptable salt thereof.
 12. The compound accordingto claim 1 which is a structure

or pharmaceutically acceptable salt thereof.
 13. A method of treatingbaldness comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim 1.